Each year about 31,000 Americans develop oral cancer. Squamous cell carcinoma accounts for 95 percent of all malignant oral lesions Oral squamous cell carcinoma is a condition that will kill approximately half of patients afflicted within five years of diagnosis. Early diagnosis is stressed, because this could increase the survival rate from 50 percent to about 80 percent. Contrast enhanced diagnostic applications of fluorescence spectroscopy may offer an effective means for early, non-invasive and rapid detection of epithelial neoplastic transformation. Our goal is to develop a unique spectroscopic contrast agent that can be applied topically for early detection of epithelial neoplasm using fluorescence imaging. Underlying our aims are the hypotheses that spectral information from contrast-enhanced fluorescence images of oral lesions can be used as a reliable approach toward accurate and early non-invasive detection of pre-malignant and malignant lesions in the oral cavity. This revised proposal will focus on the development and testing of topical application of newly developed Lanthanide Chelate-based contrast agent to induce selective accumulation of a fluorescing dye in malignant transformed epithelial tissue for the purpose of early lesion detection. Our preliminary work has shown: (1) promising correlation between the spectral information observed in contrast-enhanced fluorescence and pathological state of the lesion in the early stage of development, and (2) the ability of malignant oral lesions to selectively accumulate the contrast agent as compared to benign lesions or normal tissue. We propose to synthesize a new contrast agent that can be excited in the region of 3 10-330 nm and perform cellular and in vivo studies to; (1) optimize the chemical structure and spectroscopic properties of the dye for safe and practical applications, (2) better understand the cellular and morphological basis for the observed selective uptake of the dye by pre-malignant and malignant oral tissues, and (3) examine the diagnostic power of the proposed contrast enhanced approach as compared to other techniques as well as histopathlogical findings in a series of pre-clinical animal studies. The knowledge gained from this study may lead to the development of a simple, inexpensive and non-invasive diagnostic tool for detection and screening of oral cancer in a dentists office, guiding the biopsy and follow up of suspicious oral lesions by otolaryngologists and oral surgeons.